A targeted drug delivery method is a drug delivery method that allows a drug to be accumulated selectively and quantitatively in a target organ or tissue regardless of administration methods and sites. This delivery method can maximize the therapeutic effect of a drug by increasing the concentration of the drug in the target site, while it can minimize side effects by reducing the concentration of the drug in non-target tissues and organs. In addition, it can significantly reduce not only the amount of therapeutic drug required to achieve a therapeutic effect, but also the cost required for treatment.
There are two strategies for the targeted drug delivery. One of them is to concentrate drug carrier into specific site by controlling it physically. There have been developed magnetic nanoparticles, in which a magnetic substance, such as magnetite, and a drug are encapsulated with a polymer. When such magnetic nanoparticles are injected into a patient, and then an external magnetic field is artificially applied to the target site, the nanoparticles are localized to the target site, so that the drug loaded in the nanoparticles is released, thus exhibiting therapeutic effects. However, in this method, it is required to know the accurate location of disease in advances and the instrument to generate high magnetic field locally is also needed.
The other is to make drug carrier delivered to target site by conjugating a ligand such as antibody, glycoprotein, etc., which can bind to a substance, which is called as a receptor such as antigen, receptor protein, etc., on the surface of a cell to which the drug is to be delivered, to drug carrier. Due to using specific interaction between an antibody and antigen, this method has a merit to deliver drug carrier to unknown site to which the drug is to be delivered accurately. However, in order to use antibody targeting method, drug carrier is able to contain target drug, to be conjugated to target antibody easily and has a good bio-distribution. As one method for this method, there has been developed a targeted drug delivery system, in which a drug is loaded in a virus, such as an adenovirus or a retrovirus. However, the method for delivering drugs using viruses has problems in that the kind of drug is limited to protein or nucleic acid, and particularly in that viruses cause host immune reactions, which increase side effects instead of therapeutic effects.
And there has been developed a targeted drug delivery system, in which a drug is loaded in biocompatible polymer, and an antibody to a substance present on the surface of a cell to which the drug is to be delivered, is bound to the surface of polymer. Because polymer, which is compatible to body and has low immunity, is used, this drug carrier has a better bio-distribution than virus carrier. However this method to use polymer have a problem not to control the drug release pattern optionally, because the drug release pattern is dependent on polymer degradation.
Recently, since it became known that optical transmission through tissue is optimized in the near-infrared region (NIR) (i.e., 800-1200 nm), near-infrared resonant nanoshells, such as gold-coated nanoshells (Au2S) (Averitt, R. D. et al. Phys. Rev. Lett. 1997, vol. 78, p. 4217), silica-gold nanoshell particles (Loo, C. et al. Tech. in Cancer Res. & Treatment, 2004, vol. 3, p. 33) and hollow gold nanoshells (Chen, J. et al. Nano Lett. 2005, vol. 5, p. 473), have been widely studied in the biomedical field.
Generally, the surface plasmon-resonance frequency of solid metal nanoparticles is located in the visible range. However, metallic nanoshells show the flexibility of regulating the resonance frequency from the visible range to the NIR range, as the thickness thereof is varied. Since such metallic nanoshells strongly absorb NIR light and convert the optical energy of the absorbed light to heat, they can be used in thermal therapy and photothermally modulated drug delivery.
L. R. Hirsh et al. demonstrated that silica-gold nanoshells can be used to deliver therapeutically effective heat in an amount capable of killing only target cells, without causing damage to normal cells through excessive local heating (Hirsh, L. R. et al. Proc. Natl. Acad. Sci. USA 2003, vol. 100, p. 13549). Also, S. R. Sershen et al. demonstrated that a poly-NIPAAm-co-AAm/AU—Au2S nanoshell composite performs reversible phase transition in response to NIR radiation and promotes drug release from the composite hydrogel immediately after NIR radiation (Sershen, S. R. et al. J. Biomed. Mater. Res. 2000, vol. 51, p. 293).
However, because the NIPAAm-co-AAm hydrogel contains acrylamide (AAm), known to be a toxic substance, it has a problem of low biocompatibility. In particular, acrylamide is known to have adverse affects on male reproductive organs and renal or nervous cells, and is designated a presumed carcinogenic substance in the Industrial Safety and Health Act.